1. Field of the Invention
This invention relates to compositions containing indole and indole derivatives, and a method for treatment of inflamation caused by herpes virus, including herpes zoster, herpes simplex I and herpes simplex II, using the aforesaid compositions.
2. Background of the Related Art
Since the middle ages, physicians have used urine for healing of various infectious diseases. The medical reference book Studio Medico-Chiurgico, by Dr. Samuel Schaarschmidt, published in 1760 reveals, at pages 348-349 that lesions caused by Gonorrhea may be healed in their early stages by washing the lesions repeatedly with urine, lime water or a mixture of both. The treatment and prevention of venereal infections using urine, continued until the end of World War II. During that time, physicians advised soldiers to urinate after intercourse and if possible to wash their penis with urine.
The use of urine as a remedy to treat and prevent infectious diseases inspired the inventor to investigate the therapeutic qualities of the constituents of urine.
The Table of Urinary Values, in the CRC Handbook of Clinical Laboratory Data (Second Edition 1968) published by the Chemical Rubber Company (CRC) at pages 17 through 20 shows that urine specimens collected over a 24 hour period contained the following indole derivatives:
______________________________________ Amount Collected Indole or Indole Derivative per 24 hr. period ______________________________________ 5-Hydroxyindole acetic acid 2-9 mg Indican (3-Indoxylsulfate 40-150 mg potassium salt) Indole-total 240-350 mg Indole-3-acetic acid-free 4-8 mg Indole-3-acetic acid-total 6-13 mg Nicotinic acid, a product of 1160-1540 ug/liter inodole derivatives ______________________________________
The concentration of indican in urine varies between 40 and 150 mg per 24 hour period. This variation in the concentration of indican, indole and other indole derivatives in urine caused a large variation in the therapeutic results which were observed when lesions were treated using urine. The therapeutic value of a 40 mg-per 24 hours concentration of indican in urine does not provide any significant healing of a lesion, however, a concentration of 150 mg per 24 hours of indican in urine may have very good healing power.
The discovery and identification of indole and its derivatives in urine has proceeded as follows:
1. Indole was first prepared by Weissgerber in 1910 (Ber. 43, 3520, 1910). It was was identified in urine by Seifer, A. and Gerstenfeld, S. in 1964 (Clin. Chem., 10, 321, 1964).
2. Indican was first prepared by Baeyer (Ber. 14, 1745, 1881). It was first identified in urine by Sharlit, H. in 1932 (J. Biol. Chem. 99, 537, 1932).
3. Nicotinic acid was first identified in urine by Baker, H., Frank, O., Pasher, I., Hutner, S. H. and Sobotka, H., in 1960 (Clin. Chem. 6, 572, 1960).
4. Indole-3-acetic acid was recognized as the principal auxin of higher plants, and was prepared by Johnson and Crosby in 1963 (J. Org. Chem. 28, 1246, 1963). It was first identified in urine in 1964 by Seifer, A. and Gerstenfeld, S., (Clin. Chem. 10, 321, 1964).
A study of the literature revealed that the scientists mostly ignored indole and its derivatives contained in urine, feces and blood plasma. In the Textbook of Organic Chemistry, by E. Wertheim (1939 at pages 725-726) the following explanation for the formation of Indican was given:
"Detoxication.--Protein matter which escapes digestion in the small intestine normally undergoes bacterial putrefactive changes in the large intestine. A great number of substances, some of which are toxic in their nature, are formed as a result of the complete breakdown which takes place during this action. Among these are fatty acids, indole, skatole, phenol, phenylacetic and phenylpropionic acids, carbon dioxide, hydrogen sulfide, methane, ammonia, hydrogen, and other compounds.
"Indole and skatole are absorbed by the intestine and later eliminated in part in the urine, after being oxidized to indoxyl and skatoxyl respectively, and combined with sulfuric acid: ##STR1## phenol and cresol are eliminated in the urine partly free, partly conjugated with sulfuric acid: ##STR2##
"The amount of indican the urine gives in approximate index of the protein purification in the intestine."
The Physicians' Desk Reference (PDR) has 34 categories of dermatological preparations, including antibacterial and antifungal. However, there is no "antiviral" heading. The three anti-inflammatory agents listed all utilize a corticosteroid as their active ingredient. However, they do not heal the inflammations or lesions produced by the Herpes viruses.
None of the listed salves, ointments, foams, lotions or other materials intended for topical use employ Indole or derivatives of Indole such as Indomethacin, Tryptophan, Indole-3-propionic acid, Indole-3-acetic acid, Indole-2-carboxylic acid or Tryptophol. Mercks Manual of Diagnosis and Therapy suggests that for Herpes Simplex I and II, topical use of Idoxuridine (IDU) for herpetic keratitis (eye infection) may be effective. In addition, Mercks mentions Acyclovir as having shown promise in the treatment of Herpes lesions.
For other Herpes lesions, Mercks suggests `drying lotions` such as Camphor Spirit or 70% alcohol. For Herpes Zoster, Mercks states: "there is no known specific therapy."
Proteolytic enzymes which attack and degrade proteins, while claimed to have anti-inflammatory effects have no effect on Herpes inflammations or lesions.
Hormones which directly or indirectly cause the adrenal cortex to produce and secrete sterois, represent another class of anti-inflammatory compounds. However, no known hormones have produced a satisfactory response in the treatment of Herpes inflammations or lesions.
Inglot TOPICAL TREATMENT OF CUTANEOUS HERPES SIMPLEX IN HUMANS WITH THE NON-STEROID ANTIINFLAMMATORY DRUGS: MEFENAMIC ACID AND INDOMETHACIN IN DIMETHYLSULFOXIDE, Archivum Immunologiae et Therapiae Experimentalis, 18, 555 (1971) used Indomethacin, an Indole-containing compound, and Mefenamic acid a non-Indole containing compound in a highly toxic carrier, dimethylsulfoxide (DMSO) to treat Herpes sores. Inglot chose the carrier DMSO because it was a vehicle which ". . . facilitates their penetration into the skin." Inglot states that she did not test the DMSO carrier alone on Herpes sores.
Eckert, U.S. Pat. No. 4,263,313, issued on Apr. 21, 1981 discloses a carrier for Indomethacin to be applied to the skin of rheumatically affected patients. The express objective of the carrier is to improve the absorption of the active compound into the skin. Eckert's objective is to get Indomethacin into the body without traversing the intestinal tract, not to treat a disease of the skin.
Silber, U.S. Pat. No. 3,629,412 issued on Dec. 21, 1971, teaches use of Indomethacin as a topical ingredient with methylsalicylate (oil of wintergreen). Silber's primary objective, like Eckert is to get Indomethacin into the body without traversing the alimentary tract, though he suggests topical effectiveness on skin inflammations generally.
Prior to this invention, there were no antiviral agents in a non-toxic base which were free from harmful side-effects and that were effective in the treatment and alleviation of pain and the inflammatory response caused by Herpes virus.